WO1996020187A3 - Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products - Google Patents

Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products Download PDF

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Publication number
WO1996020187A3
WO1996020187A3 PCT/US1995/016779 US9516779W WO9620187A3 WO 1996020187 A3 WO1996020187 A3 WO 1996020187A3 US 9516779 W US9516779 W US 9516779W WO 9620187 A3 WO9620187 A3 WO 9620187A3
Authority
WO
WIPO (PCT)
Prior art keywords
inflammatory
steroidal anti
compounds
present
oxidants
Prior art date
Application number
PCT/US1995/016779
Other languages
French (fr)
Other versions
WO1996020187A2 (en
Inventor
Mark Hellberg
Gustav Graff
Daniel A Gamache
Jon C Nixon
William H Garner
Original Assignee
Alcon Lab Inc
Mark Hellberg
Gustav Graff
Daniel A Gamache
Jon C Nixon
William H Garner
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27001775&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1996020187(A3) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US08/362,718 external-priority patent/US5607966A/en
Priority to EP95944517A priority Critical patent/EP0799219B1/en
Priority to BR9510460A priority patent/BR9510460A/en
Priority to AU46877/96A priority patent/AU689024B2/en
Priority to AT95944517T priority patent/ATE239717T1/en
Priority to DE69530702T priority patent/DE69530702T2/en
Priority to US08/849,230 priority patent/US5811438A/en
Application filed by Alcon Lab Inc, Mark Hellberg, Gustav Graff, Daniel A Gamache, Jon C Nixon, William H Garner filed Critical Alcon Lab Inc
Priority to CA002207574A priority patent/CA2207574C/en
Priority to MX9704671A priority patent/MX9704671A/en
Priority to JP52055096A priority patent/JP4021935B2/en
Publication of WO1996020187A2 publication Critical patent/WO1996020187A2/en
Publication of WO1996020187A3 publication Critical patent/WO1996020187A3/en
Priority to FI972621A priority patent/FI119474B/en
Priority to NO972879A priority patent/NO972879L/en
Priority to KR97000704302A priority patent/KR19980700975A/ko
Priority to CL2010000383A priority patent/CL2010000383A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Abstract

The compounds of the present invention are of the formula (I): A-X-(CH2)n-Y-(CH3)m-Z wherein: A is an non-steroidal anti-inflammatory agent (NSAIA); A-X is an ester or amide linkage derived from the carboxylic acid moiety of the NSAIA, wherein X is O or NR; R is H, C1-C6 alkyl or C3-C6 cycloalkyl; Y, if present, is O, NR, C(R)2, CH(OH) or S(O)n'; n is 2 to 4 and m is 1 to 4 when Y is O, NR, or S(O)n'; n is 0 to 4 and m is 0 to 4 when Y is C(R)2 or is not present; n is 1 to 4 and m is 0 to 4 when Y is CH(OH); n' is 0 to 2; and Z is (a), (b), (c), (d) or (e) wherein: R' and R3 are H, C(O)R, C(O)N(R)¿2, PO3?-, or SO¿3?-; R' is H or C¿1?-C6 alkyl; and R' and R?3¿ together may form a ring having structure: (1) or (2); and provided that when Z is (e), X is not O. The compounds of the present invention also include pharmaceutically acceptable salts of the compounds of formula (I). Methods for treating inflammatory pathologies are disclosed. Particularly, the methods utilize pharmaceutical compositions containing certain compounds having an anti-inflammatory and anti-oxidant moiety covalently linked by an amide or ester bond. The compounds are useful in preventing and treating inflammatory disorders through several mechanisms.
PCT/US1995/016779 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products WO1996020187A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
MX9704671A MX9704671A (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products.
JP52055096A JP4021935B2 (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids that can be used as antioxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
CA002207574A CA2207574C (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
AU46877/96A AU689024B2 (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
AT95944517T ATE239717T1 (en) 1994-12-23 1995-12-21 ESTERS AND AMIDES OF NON-STEROIDAL ANTI-INFLAMMATORY CARBOXIC ACIDS WHICH CAN BE USED AS ANTI-OXIDANTS 5-LIPOXYGENASE INHIBITORS AND NON-STEROIDAL ANTI-INFLAMMATORY AGENTS
DE69530702T DE69530702T2 (en) 1994-12-23 1995-12-21 ESTERS AND AMIDES OF NON-STEROIDAL ANTI-FLAMMABILITY CARBONIC ACIDS THAT CAN BE USED AS AN ANTI-OXIDANTS 5-LIPOXYGENASE INHIBITORS AND NON-STEROIDAL ANTI-FLAMMABILITY AGENTS
US08/849,230 US5811438A (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
EP95944517A EP0799219B1 (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
BR9510460A BR9510460A (en) 1994-12-23 1995-12-21 Non-steroidal anti-inflammatory carboxylic acid amide esters that can be used as 5-lipoxygenase-inhibiting antioxidants and non-steroidal anti-inflammatory products
FI972621A FI119474B (en) 1994-12-23 1997-06-18 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which can be used as antioxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
NO972879A NO972879L (en) 1994-12-23 1997-06-20 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which can be used as antioxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
KR97000704302A KR19980700975A (en) 1994-12-23 1997-06-23
CL2010000383A CL2010000383A1 (en) 1994-12-23 2010-04-19 Esters and amide of carboxylic acids containing a non-steroidal anti-inflammatory agent; pharmaceutical composition: and its use as 5-lipoxygenase inhibitors to prevent or relieve tissue edema, inflammation and congestion of the conjunctiva, corneal clouding and damage to ophthalmic tissues (divisional sol. 3109-99).

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/362,718 1994-12-23
US08/362,718 US5607966A (en) 1994-12-23 1994-12-23 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory prodrugs
US08/472,445 US5643943A (en) 1994-12-23 1995-06-07 Systemic administration of esters and amides of antioxidants which may be used as antioxidant prodrug therapy for oxidative and inflammatory pathogenesis
US08/472,445 1995-06-07

Publications (2)

Publication Number Publication Date
WO1996020187A2 WO1996020187A2 (en) 1996-07-04
WO1996020187A3 true WO1996020187A3 (en) 1996-12-12

Family

ID=27001775

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/016779 WO1996020187A2 (en) 1994-12-23 1995-12-21 Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products

Country Status (16)

Country Link
US (2) US5643943A (en)
EP (1) EP0799219B1 (en)
JP (1) JP4021935B2 (en)
KR (1) KR19980700975A (en)
CN (2) CN1169805C (en)
AT (1) ATE239717T1 (en)
AU (1) AU689024B2 (en)
CA (1) CA2207574C (en)
CL (1) CL2010000383A1 (en)
DE (1) DE69530702T2 (en)
ES (1) ES2199262T3 (en)
FI (1) FI119474B (en)
HK (1) HK1039617B (en)
MX (1) MX9704671A (en)
NO (1) NO972879L (en)
WO (1) WO1996020187A2 (en)

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